Keystone Epitope Theory: An Ecological Perspective on RNA Viruses, Tumor Immunoediting, and Vaccine Design

Abstract

We propose that persistent, human-adapted DNA organisms shape postnatal immunity by focusing responses on functionally constrained epitopes within tissue niches. Here, we examine rapidly evolving RNA viruses and tumors through that lens. We propose that their persistence is promoted by 2 coupled mechanisms: (i) immunodominance steering toward mutable “decoy” epitopes that contribute little to durable control, and (ii) antigen display control that reduces cytotoxic T lymphocyte (CTL) recognition while preserving inhibitory natural killer (NK) receptor engagement, for example via HIV Nef/Vpu effects on HLA-A and HLA-B and through HLA-E/NKG2A pathways. Tumors show analogous vulnerabilities through altered class I expression and reinforcement of inhibitory signaling. Using HIV as the primary model, we distinguish HLA-associated viral adaptation mechanisms and highlight evidence consistent with a subset of adaptations that preserve detectable T-cell recognition while being associated with reduced antiviral effector function. We then consider the degree to which this framework can be extended to hepatitis C virus (HCV), influenza, SARS-CoV-2, and tumor immunoediting. We conclude with 3 vaccine design principles: prioritize epitopes where substitutions carry measurable fitness costs, avoid immunogens dominated by mutable targets, and account for antigen presentation context and inhibitory NK signaling when evaluating epitope choice. We distinguish established observations from testable predictions and outline experiments needed to evaluate the framework. We frame the analysis conditionally on the keystone-imprinting premise, which is developed in companion work.